WO2012123229A1

WO2012123229A1 - Solid, negative x-ray contrast medium for depicting the gastrointestinal tract

Info

Publication number: WO2012123229A1
Application number: PCT/EP2012/053074
Authority: WO
Inventors: Ulrich Speck; Matthias Bräutigam; Melanie Biedermann
Original assignee: Innora Gmbh
Priority date: 2011-03-11
Filing date: 2012-02-23
Publication date: 2012-09-20
Also published as: DE102011005444A1

Abstract

The invention relates to a solid X-ray contrast medium comprising microspheres for depicting the gastrointestinal tract, with a cavity volume of at least 25% of the total volume, the cavity containing at least one gas, and the medium being characterized in that the microspheres are embedded in a dry binder. The invention further relates to the production of this X-ray contrast medium and also to its use.

Description

Solid, negative X-ray contrast agent for imaging the

Gastrointestinal tract

The present invention relates to a solid X-ray contrast agent for displaying the gastrointestinal tract comprising microspheres having a void volume of at least 25% of the total volume, wherein in the cavity at least one gas is contained and which is characterized in that the microspheres are embedded in a dry binder.

Soft tissues such as those of the gastrointestinal tract are reproduced only insufficiently with normal radiographic methods, which is why the administration of contrast media is required. X-ray contrast agents (also referred to as "contrast agent" in the following) increase the contrast of organs and organ systems with the aim of differentiating between tissues of similar radiopacity The increase in contrast may be due to substances of low or absent absorption, so-called negative contrast agents, or by substances of high absorption, Examples of negative contrast agents are air and gases, which do not absorb x-rays and therefore appear black compared to the soft tissues in the x-ray Positive positives are less permeable to x-rays than soft tissue and therefore appear white in the image.

In computed tomography (CT), the Hounsfield scale is used for measurements in order to describe the location-dependent attenuation of the X-radiation by absorption in the tissue and to display it as a gray-scale image. The CT number or the CT value is given in Hounsfield units (HE or Hounsfield units, HU). By definition, water has a value of 0 HU. Air almost does not absorb X-rays and has a CT count of -1000 HU. Fat tissue absorbs X-rays a little less than water and has about -100 HU. Depending on the density (calcium content), bones have HU values of +500 to +1500 HU.

Imaging of the upper gastrointestinal tract is often accomplished with the aid of oral contrast agents which have increased electron density, for example

Barium sulfate or iodine-containing contrast agents (positive contrast agents), as well as with help conventional or digital X-ray techniques such as computed tomography. The imaging of the colon is usually done by barium enema.

Barium sulfate, however, has some disadvantages. In particular, positive contrast agents can not always differentiate wall changes, for example in tumors. Likewise, they do not allow for improved visualization of the intestinal wall by additional intravenous administration of a positive contrast agent.

So far, oils have been studied as negative contrast agents because fats have a significantly lower absorption than water. In 1992, Malik et al. (Malik N, Khandelwal N, Garg K, Suri S, Australas Radiol 1992 Feb; 36 (1): 31-3.) The successful application in humans of oil emulsions to distinguish the gastrointestinal tract and the mucosal and mural visualization. However, this method has never been clinically developed and is now obsolete due to poor patient acceptance and high fat loading.

For the first time in 1991, Unger proposed the use of homogeneous aqueous suspensions of microspheres as an oral contrast medium for CT, whereby the microspheres have a low density (see WO 1992/017514 A1). However, no clinically useful contrast agent has ever been developed on this basis. Aqueous suspensions are heterogeneous mixtures of water and finely divided solids, which are often suspended in the liquid. Suspensions are thermodynamically unstable and often require additional components to keep the suspension stable. Such systems involve several limitations that hinder the development and approval of the competent authorities. The stability of the aqueous suspensions is limited and simple sterilization is not possible. Furthermore, the patient must be administered a large volume of the suspension, which is cumbersome for this. In addition, aqueous suspensions require a complicated pharmaceutical formulation which complicates development, among other things because time-consuming and costly stability tests must be performed.

The volume of negative contrast agent required for imaging after oral administration is dependent on the gas content of the selected formulation. tion. Unger describes a maximum gas content of his liquid formulations, but this would lead to a very high volume to be recorded for the patient.

The object of the present invention was to provide an X-ray contrast agent which overcomes the above-mentioned disadvantages, i. in particular has an improved stability to the aqueous suspensions, is a simple pharmaceutical preparation formulation and is therefore suitable for approval by the competent authorities and the clinical application.

The object is achieved by a fixed X-ray contrast agent for displaying the gastrointestinal tract, which in a preferred form comprises microspheres with a void volume of at least 25% of the total volume, wherein at least air or another gas is contained in the cavity and which is characterized in that the microspheres embedded in a dry binder. Preferably, the word "comprise" here means "consist of", i. the solid X-ray contrast agent preferably consists of microspheres with a void volume of at least 25% of the total volume, wherein the cavity contains at least air or another gas embedded in a dry binder. The same applies to the preferred embodiments shown below. The solid X-ray contrast agent is preferably used for enteral administration. The term enteral refers to the delivery or loss of drugs or food, electrolytes or trace elements via the intestine. Enteral access routes are therefore the mouth (oral) and the rectum (actually rectum, therefore rectal access routes). Enteral administration may be by gavage, PEG tube or PEJ. Particularly preferred is the use of the solid X-ray contrast agent for oral or rectal administration.

The dry binder is preferably a dried agglutinating agent or a pudding or jelly powder having at least one gelling agent. In the case of the dried agglutinating agent, the microspheres are embedded therein in a solid matrix formed by the agglutinating agent. In the case of the pudding or jelly powder as a binder, the microspheres are present in non-demixable form. "Non-demixable" means that no separation takes place even after prolonged mechanical action (shaking). The binder may contain additional substances such as mannitol and / or flavorings. The primary goal is to pack as dense a package as possible

To reach the microspheres, which are then taken by the patient (possibly with a little liquid). Since these microspheres contain gas (s), it is a negative contrast agent. An essential difference to gas in foods, e.g. foamed chocolate, is that the gas occlusive material of the microspheres is stable and is not water-soluble or digestible, thus ensuring imaging along the entire gastrointestinal tract by the negative contrast.

The agglutinating agent enables the improved cohesion of the individual microspheres in the solid preparation. It must have agglutinating properties and preferably a pleasant or at least neutral taste for oral administration and be toxicologically safe. It may be a natural product such as a vegetable or fruit pulp, sugars (for example, sucrose) or sugar derivatives (for example, sugar alcohols such as mannitol) or syrup or chocolate, or a synthetic product. "Sugars" here include both mono- and Di-saccharides Preference is given to vegetable or fruit pulp or their combination, particularly preferably fruit pulp based on fruit, cereal or maize flour, in particular applesauce, but also better defined substances such as proteins, polysaccharides or fats are also preferred.

Another preferred embodiment is a non-separable pulverulent coating, on the one hand microspheres and on the other hand a pudding or

Contains jelly powder. This pudding or jelly powder contains at least one gelling agent, e.g. Carrageenan or gelatin. Other food-containing additives (e.g., egg whites, preservatives) may be included (such as in instant cream puddings or jellies). The same applies to stabilizers, emulsifiers etc. commonly used in foods. This non-demixable pulverulent spread is mixed with a liquid only before application. The initial mass or cream (pudding, porridge jelly, e.g., jelly) is then ingested by the patient.

The term "gelling agent" is synonymous with "thickening agent". This refers to food additives which swell or bind with water, that is to say by thickening a wished to give consistency. In the present context, only the gelling agents acceptable from a food-technical point of view are included here. These are primarily made of polygons or vegetable or animal proteins. Preferably mentioned are agar-agar (E 406), alginic acid (E 400), ammonium alginate (E 403), calcium alginate (E 404), potassium alginate (E 402), sodium alginate (E 401), pectin (E 440), amidated pectin (E 440N), carrageenan (E 407), furcellaran (E 407 assigned), gelatin, gellan (E 418), guar gum (E 412), gum arabic (E 414), locust bean gum (E 410), karaya (E 416) , Propylene glycol alginate (E 405), tara gum (E 417), tragacanth (E 413), xanthan (E 415) and modified starches.

For the purposes of the present invention, "microspheres" are hollow bodies with a void volume of at least 75% of the total volume of the individual microsphere which contain at least one gas in this void The term "at least one gas" comprises pure gases and gas mixtures of two or more gases. The at least one gas is preferably selected from air, carbon dioxide, oxygen, nitrogen, helium, neon, argon or xenon, any at room temperature (20 ° C) gaseous organic compounds such as hydrocarbons, or halogenated, preferably fluorinated hydrocarbons. Gaseous hydrocarbons at room temperature are preferably CrC ₅ -hydrocarbons which are branched or unbranched (methane to pentane). Particularly preferred are air, isobutane and isopentane. This includes microspheres which have the gas / gases distributed over several cavities, ie for example microspheres made of styrofoam. Also included are microspheres, which have inside a single filled with gas / gases central cavity. The latter, ie microspheres with an internal central cavity, are preferred. Such microspheres are generally described, for example, by Unger in US Pat. No. 6,528,039 B2. In particular with regard to the materials of the microspheres (biocompatible, metabolically stable and slowly biodegradable natural and synthetic polymers or copolymers, eg cyanoacrylates, polylactides) and their preparation, reference is made inter alia to this document. The density of the microspheres is preferably less than 0.1 g / cm ³ . More preferably, the density of the microspheres is between 0.020 and 0.10 g / cm ³ , most preferably less than 0.050 g / cm ³ .

The outer diameter, ie the size of such microspheres is preferably 1 to 500 μηι. Preferably, the microspheres have no uniform outer Diameter, but there is a size distribution between 1 and 500 μηι, preferably between 10 to 250 μηι, more preferably between 10 and 100 μηι, in the sense of a normal distribution. Accordingly, the average outer diameter between 1 and 500 μηι, preferably between 10 and 250 μηι, more preferably between 10 and 100 μηι. A non-uniform size distribution allows a denser packing in the solid form. Optionally, a greater variance in size distribution may be desirable.

Suitable microspheres are commercially available, for example, under the trade name Expancel® from AkzoNobel. Examples include Akzo Nobel Expancel® 551 DE 40 d42 with a density of 0.042 ± 0.004 g / cm ³ and an average outer diameter of 40 μm (30-50 μm) or Akzo Nobel Expancel® 461 DET 40 d25 with one density of 0.025 ± 0.003 g / cm ³ and an average outer diameter of 40 μηι (35-55 μηι) or Akzo Nobel Expancel® 461 DET 80 d25 with a density of 0.025 ± 0.003 g / cm ³ and a mean outer diameter of 80 μηι (60-90 μι ι), or expander 092 DET 100 d25 with a density of 0.025 ± 0.003 g / cm ³ and a mean diameter of 80-120 μηι.

The microspheres preferably consist of a biocompatible and toxicologically harmless synthetic polymer or copolymer as described by Unger in US Pat. No. 6,528,039 B2. They may have a surface modification that enhances the solid state agglutination properties, but must ensure rapid separation of the microspheres when ingested by the patient with a liquid or in the gastrointestinal fluids.

The shell of the microspheres is preferably flexible and smooth, so that compression with deformation during the drying process of the X-ray contrast agent with dried agglutinating agent is possible. This allows a further reduction of the space requirement and thus a reduction in the density of the X-ray contrast agent and improves patient acceptance.

European Pharmacopoeia excipients such as disintegrants may also be included in the solid X-ray contrast agent to achieve rapid release and distribution of microspheres in the gastrointestinal tract after ingestion. Furthermore, non-absorbable or poorly absorbable osmo-active substances such as mannitol or sorbitol may be included. These give an initale

Hyperosmolarity in the gastrointestinal tract, which improves CT imaging via extension of the gastrointestinal tract.

The preparation of the solid X-ray contrast medium, which comprises microspheres in a matrix of dried agglutinating agent, takes place in such a way that the

Microspheres are mixed with an agglutinating agent, the mixture is molded and / or pressed into a predetermined shape and then dried. Preferably, temperatures of up to 40 ° C, more preferably between 20 and 30 ° C are used for the drying. Alternatively, a freeze or spray drying can take place. There are no restrictions on the shape and size of the compacts. The pellets can be crushed and encapsulated as beads or granules or coated like dragees to protect against premature decay.

In a preferred embodiment, at least one further evaporation solvent is additionally added to the mixture of microspheres and agglutinating agent, which is, for example, water. In particular, when using vegetable or fruit pulp as agglutinating agent, water is preferred as an additional evaporating agent, since the pulp also contain water and water is harmless from a food-technical point of view. Other preferred liquids for flooding and mixing the components prior to molding and drying are volatile, low dose, nontoxic solvents such as ethanol.

Preferably, the mixture is sterilized before or after drying, whereby most common sterilization methods can be used, preferably by means of ethylene oxide.

In the powder preparation, the microspheres are uniformly mixed with the pudding or jelly powder. This mixture does not separate even after prolonged storage or after transport, even by mechanical shocks, it is virtually unmemable. The solid X-ray contrast agent has a minimal content of agglutinant or pudding / jelly powder or other excipients. This allows a high content of gas (s) and thus increases the efficiency of this negative X-ray contrast agent. Preferably, at least 50% (VA /), more preferably at least 70% (VA), most preferably at least 90% (VA /) of the solid X-ray contrast agent is encapsulated gas (s), and the capsule material is not during the gastrointestinal passage dissolved, digested or degraded.

The solid X-ray contrast agent based on the dried agglutinating agent can also be converted into granular pharmaceutical formulations by careful comminution and suitable screening methods. The solid X-ray contrast agent is then preferably in the form of tablets or granules, wherein granules preferably also include pellets (spherical or cylindrical shape, preferably spherical shape). These forms can be encased or coated by established pharmaceutical procedures.

The X-ray contrast agent in its solid form is stable in storage and transport. For administration to the patient, the solid forms based on the dried agglutinating agent, for example pellets, may be taken with some water. The powder preparation is mixed with a liquid before application. After the stiffening or solidification of the powder or jelly, the solidified mass, the porridge or the firm cream is taken by the patient.

Use is made of the above-described solid X-ray contrast agent, in particular in X-ray imaging of the gastrointestinal tract. Administration is enteral, preferably oral or rectal. To improve the imaging of the wall of the gastrointestinal tract, a positive extracellular X-ray contrast agent can additionally be administered intravenously. Its administration improves the contrast between the gastrointestinal lumen containing the negative X-ray contrast agent of the invention and the perfused blood-labeled gastrointestinal wall. Description of the pictures

Figure 1 shows whole body CT images of rats given a formulation of Akzo Nobel Expancel® 551 DE 40 d42 balls in dried applesauce. The solid contrast agent was prepared for administration in an animal experiment by gavage with a little water to a slurry. A control rat (Tier 3) received applesauce without microspheres. The whole-body CT images show a very well-visible blackened rat stomach with a smooth stomach wall (animals 1, 2, 4.5), which does not show up in the CT image of the control animal (animal 3 only applesauce).

The invention will be explained below with reference to examples.

Examples

example 1

A solid formulation of Akzo Nobel Expancel® 551 EN 40 d42 microspheres and applesauce was prepared by mixing three volumes of microspheres with one volume of applesauce. From the mixture (the slurry) cubes were molded with volumes of about 4-5ml and dried at room temperature (20 ° C) for three days. The density of a dried cube was about 0.26 g / cm ³ .

A formulation with Akzo Nobel Expancel® 551 DE 40 d42 balls in applesauce was prepared as indicated above. The solid contrast agent (volume about 4-5 ml per test animal) was prepared for administration in an animal experiment through a nasogastric tube with a small amount of water to form a gavage that was common in the stomach. Rats weighing about 250g were deprived of food for 12 hours. Subsequently, about 4-5 ml of the porridge was administered to the rats via a probe into the stomach (animals 1, 2, 4, 5). A control rat received 4-5ml applesauce (Tier 3). All rats were anesthetized. Approximately 30 minutes after the formulation or apple sauce was administered, whole body CT images were taken. The result is shown graphically in Fig. 1 and shows after application of the negative contrast agent a very visible, blackened rat stomach with smooth stomach wall (animals 1, 2, 4, 5) in the CT image of the control animal (Tier 3, only applesauce ) does not represent. Example 2

A solid formulation of Akzo Nobel Expancel® 551 DE 40 d42 microspheres and mannitol was obtained by mixing 1.18 g of mannitol, about 30 ml of mirospheres, and 5 ml of water. From the mixture (the slurry) cubes were formed with a volume of about 5ml and dried at room temperature for three days. The density of a dried cube was 0.12 g / ml.

Example 3

A powder formulation for direct preparation before ingestion by the patient was prepared as follows. 10 g of a finished cream pudding powder, here paradise cream Oetker (contains as emulsifier mono- and diglycerides of fatty acids and as gelling agents carrageenan) were mixed with 25 ml Akzo Nobel Expancel® 551 DE 40 d42 microspheres. For the application, the finished mixture was made up to 50 ml with milk and stirred. After solidification, a semi-solid cream was present.

Claims

claims

1. A solid X-ray contrast agent for displaying the gastrointestinal tract comprising microspheres having a void volume of at least 25% of the total volume, wherein in the cavity at least one gas is contained, characterized in that the microspheres are embedded in a dry binder.

2. A solid radiographic contrast agent according to claim 1, characterized in that the dry binder is a dried agglutinating agent, wherein the microspheres are embedded in a solid matrix.

3. A solid radiographic contrast agent according to claim 1, characterized in that the dry binder is a pudding or jelly powder having at least one gelling agent.

4. A solid radiographic contrast agent according to any one of claims 1-3, characterized in that at least 50%, more preferably at least 70%, most preferably at least 90% of the solid X-ray contrast agent are the at least one gas.

5. A solid X-ray contrast agent according to any one of claims 1-4, characterized in that the microspheres have a mean outer diameter of 1 to 1000 μηι.

6. A method for producing a solid X-ray contrast agent, which

Microspheres having a void volume of at least 25% of the total volume, wherein at least one gas is contained in the cavity, the microspheres being embedded in a solid matrix based on a dried agglutinating agent, characterized in that the microspheres are mixed with an agglutinating agent, the mixture is shaped into a predetermined shape and then dried.

7. The method according to claim 6, characterized in that the mixture of microspheres and agglutinating agent at least one further Evaporationslö- sungsmittel is additionally added.

8. The method according to claim 6 or 7, characterized in that the mixture is sterilized before or after drying.

9. The method according to any one of claims 6-8, characterized in that a pressure-resistant container is used for the shaping.

10. Use of a solid X-ray contrast agent, which microspheres with a void volume of at least 25% of the total volume, wherein in the cavity at least one gas is contained, which are embedded in a dry binder, for X-ray imaging of the gastrointestinal tract.

1 1. Use according to claim 10, wherein the application is carried out orally or rectally.

12. Use according to claim 10 or 1 1, characterized in that in addition a further X-ray contrast agent is administered extracellularly intravenously.